Adventitial delivery of dominant-negative [p67.sup.phox] attenuates neointimal hyperplasia of the rat carotid artery

Several essential components of NADPH oxidase, including [p22.sup.phox], [gp91.sup.phox] (nox2) and its homologs nox1 and nox4, [p47.sup.phox], [p67.sup.phox], and rac1, are present in the vasculature. We previously reported that [p67.sup.phox] is essential for adventitial fibroblast NADPH oxidase [O.sup.-.sub.2] production. Thus we postulated that inhibition of adventitial [p67.sup.phox] activity would attenuate angioplasty-induced hyperplasia. To test this hypothesis, we treated the adventitia of carotid arteries with a control adenovirus (Ad-control), a virus expressing dominant-negative [p67.sup.phox] (Ad-p67dn), or a virus expressing a competitive peptide (gp91ds) targeting the [p47.sup.phox]-[gp91.sup.phox] interaction (Ad-gp91ds). Common carotid arteries (CCAs) from male Sprague-Dawley rats were transfected with Ad-control, Ad-p67dn, or Ad-gp91ds in pluronic gel. After 2 days, a 2-F (Fogarty) catheter was used to injure CCAs in vivo. After 14 days, CCAs were perfusion-fixed and analyzed. In 13 experiments, digital morphometry suggested a reduction of neointimal hyperplasia with Ad-p67dn compared with Ad-control; however, the reduction did not reach statistical significance (P = 0.058). In contrast, a significant reduction was achieved with Adgp91ds (P = 0.006). No changes in medial area or remodeling were observed with either treatment. Moreover, adventitial fibroblast proliferation in vitro was inhibited by Ad-gp91ds but not by Ad-p67dn, despite confirmation that Ad-p67dn inhibits NADPH oxidase in fibroblasts. These data appear to suggest that a multicomponent vascular NADPH oxidase plays a role in neointimal hyperplasia. However, inhibition of [p47.sup.phox] may be more effective than inhibition of [p67.sup.phox] at attenuating neointimal growth. NADPH oxidase; [p47.sup.phox]; adventitia; restenosis